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Macrolides (see Table 12: Bacteria and Antibacterial Drugs: Macrolides ) are primarily bacteriostatic; by binding to the 50S subunit of the ribosome, they inhibit bacterial protein synthesis.
Pharmacology
Dirithromycin is a prodrug that is converted to its active form during intestinal absorption. Except for telithromycin, macrolides are relatively poorly absorbed orally. Food has the following effects on absorption:
All macrolides diffuse well into body fluids, except CSF, and are concentrated in phagocytes. Excretion is mainly in bile.
Indications
Macrolides are active against
Bacteroides fragilis is resistant. Clarithromycin and azithromycin have enhanced activity against Haemophilus influenzae and activity against Mycobacterium avium complex.
Macrolides have been considered the drug of choice for group A streptococcal and pneumococcal infections when penicillin cannot be used. However, pneumococci with reduced penicillin sensitivity are often resistant to macrolides, and in some communities, up to 20% of S. pyogenes are macrolide-resistant. Because they are active against atypical respiratory pathogens, they are often used empirically for lower respiratory tract infections, but another drug is often necessary to cover macrolide-resistant pneumococci. Macrolides have other clinical uses (see Table 13: Bacteria and Antibacterial Drugs: Some Clinical Uses of Macrolides). Macrolides are not used to treat meningitis.
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Table 13
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| Some Clinical Uses of Macrolides |
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Drug
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Indication
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Comments
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Macrolides
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Infection due to Mycoplasma pneumoniae, Legionella sp, or Bordetella pertussis
Eradication of Corynebacterium diphtheriae in carriers
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Drugs of choice
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Symptomatic cat-scratch disease (Bartonella henselae)
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—
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Bacillary angiomatosis and peliosis hepatis in patients with AIDS (involving B. henselae or B. quintana)
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—
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Azithromycin
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Cerebral toxoplasmosis
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Used with other drugs
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Babesiosis
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Used with other drugs
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Chlamydia trachomatis urethritis and cervicitis
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—
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Clarithromycin and azithromycin
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Mycobacterium avium complex
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Part of a multidrug regimen
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Erythromycin
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Uncomplicated skin infections
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—
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Acne
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Topical use
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Bowel preparation before GI tract surgery
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Taken orally and used with an oral aminoglycoside
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Contraindications
Macrolides are contraindicated in patients who have had an allergic reaction to them.
Concomitant administration of macrolides with astemizole, cisapride, pimozide, or terfenadine is contraindicated. Postmarketing surveillance has reported cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, torsades de pointes) when clarithromycin or erythromycin was coadministered with astemizole, cisapride, pimozide, or terfenadine; this effect was most likely due to inhibition of metabolism of these drugs by erythromycin and clarithromycin. Deaths have been reported.
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Use During Pregnancy and Breastfeeding
Erythromycin and azithromycin are in pregnancy category B (animal studies show no risk and human evidence is incomplete, or animal studies show risk but human studies do not). Erythromycin is considered safer because clinical use has been much more extensive.
Clarithromycin is in category C (animal studies show some risk, evidence in human studies is inadequate, but clinical benefit sometimes outweighs risk).
Erythromycin is considered compatible with breastfeeding. Safety of other macrolides during breastfeeding is unknown.
Adverse Effects
Main concerns include
Erythromycin commonly causes dose-related GI disturbances, including nausea, vomiting, abdominal cramps, and diarrhea; disturbances are less common with clarithromycin and azithromycin. Taking the drug with food may help decrease GI disturbances. Erythromycin may cause dose-related tinnitus, dizziness, and reversible hearing loss. Cholestatic jaundice occurs most commonly with erythromycin estolate. Jaundice usually appears after 10 days of use, primarily in adults but can occur earlier if the drug has been given previously. Erythromycin is not given IM because it causes severe pain; when given IV, it may cause phlebitis or pain. Hypersensitivity reactions are rare.
Erythromycin causes QT-interval prolongation and predisposes to ventricular tachyarrhythmia, especially in women, in patients who have QT-interval prolongation or electrolyte abnormalities, and in patients taking another drug that may prolong the QT interval.
Dosing Considerations
For azithromycin and dirithromycin, no dosage adjustment is required for renal insufficiency.
Erythromycin and, to some extent, clarithromycin interact with numerous drugs because they inhibit hepatic metabolism via the cytochrome P-450 (CYP450) system. Azithromycin is the least likely to interact with other drugs. Interactions may occur when erythromycin or clarithromycin are taken with the following:
Telithromycin
Telithromycin is a ketolide antibiotic. Ketolides are chemically related to macrolides and inhibit bacterial ribosomal protein synthesis without inducing resistance to macrolides, clindamycin, or streptogramins.
Telithromycin is rapidly absorbed orally with or without food and is metabolized primarily in the liver.
Indications
Telithromycin is active against erythromycin-susceptible staphylococci and streptococci and multidrug-resistant S. pneumoniae. Telithromycin is also active against erythromycin-susceptible enterococci, Bordetella pertussis, H. influenzae, Helicobacter pylori, Moraxella catarrhalis, M. pneumoniae, C. pneumoniae, and Legionella, Prevotella, and Peptostreptococcus spp.
Because of safety concerns, telithromycin is recommended only for the treatment of adults ≥ 18 yr with community acquired mild to moderate pneumonia due to the following:
Contraindications
Contraindications include
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Use During Pregnancy and Breastfeeding
Telithromycin is in pregnancy category C because animal studies show some risk, evidence in human studies is inadequate, but clinical benefit sometimes outweighs risk.
Safety of telithromycin during breastfeeding is unknown.
Adverse Effects
Adverse effects include
Diarrhea, nausea, vomiting, and dizziness are the most common adverse effects. Prolongation of the QT interval, hyperbilirubinemia, elevation of liver enzymes, transient loss of consciousness (sometimes associated with vagal syndrome), and visual disturbances (particularly a slowed ability to accommodate and to release accommodation) are less common. Severe hepatotoxicity, which may require liver transplantation and which may be fatal, may occur.
Cross-sensitivity with macrolides can occur.
Dosing Considerations
Telithromycin inhibits cytochrome P-450 (CYP450) 3A4, increasing levels of the following drugs:
CYP3A4 inducers such as rifampin, phenytoin, carbamazepine, and phenobarbital decrease levels of telithromycin; the CYP3A4 inhibitors itraconazole and ketoconazole increase levels of telithromycin. Telithromycin decreases absorption of sotalol.
Last full review/revision July 2009 by Matthew E. Levison, MD
Content last modified April 2012
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